Relationship between severity of renal damage and erythropoietin production in uranyl nitrate-induced acute renal failure.

Adult female Wistar rats were injected with 1 mg/kg body weight of uranyl nitrate (UN). Evaluation of renal function, histopathology studies, and determination of plasma erythropoietin (Ep) titers after exposure to 456 mb for 16 h were performed at 1, 2, 7, 10, 15, and 21 days after drug injection. Plasma urea and creatinine concentrations markedly increased during the first seven days after injection, reaching maximal values on day 7 and decreasing thereafter. Significant increases in urine volume and significant depressions in urine osmolality also were observed; both alterations were most marked on day 7 after injection. A coagulative necrosis of the epithelium of proximal convoluted tubules, desquamation of the necrotic cells, and dilation or collapse of the tubular lumen were observed; the lesions were more marked on day 7. Plasma Ep levels in UN-treated rats exposed to hypobaria were markedly lower than in noninjected controls similarly exposed. Measurements were performed one, two, and seven days after UN injection, with maximal depression observed on day 7. These observations indicate that there is a correlation between the extent of both tubule damage and degree of renal dysfunction and plasma Ep production during exposure to hypoxia in UN-treated rats. This suggests that the renal Ep component is derived primarily from tubular cells.

Effect of glucocorticoids on renal dopamine production.

This study assess the effects of glucocorticoids on dopamine excretion and evaluates the participation of renal dopamine in the effects of glucocorticoids on renal function and Na+ excretion. Dexamethasone (i.m.; 0.5 mg/kg) was administered to male Wistar rats on day 2 or on days 2 and 5. Daily urinary excretions of Na+, dihydroxyphenylalanine (DOPA), dopamine and dihydroxyphenylacetic acid were determined from day 1 to day 7. Renal function was evaluated 8 h after dexamethasone administration in a separate group. The first dose of dexamethasone increased about 100% diuresis and natriuresis, increased urinary DOPA and renal plasma flow, and did not affect urinary dopamine or the other parameters evaluated. These effects were not affected by previous administration of haloperidol. The second dexamethasone dose increased about 200% diuresis and natriuresis, increased urinary dopamine, DOPA, dihydroxyphenylacetic acid, Uosm x V and both glomerular filtration rate and renal plasma flow. Carbidopa administered before the second dexamethasone dose blunted both the diuretic and the natriuretic response whereas haloperidol abolished or blunted all the effects of the second dexamethasone dose. These results show that modifications in renal dopamine production produced by corticoids may contribute to the effects of these hormones on Na+ balance and diuresis and suggest that regardless the factor that promotes an increase in renal perfusion and glomerular filtration rate during long term administration of glucocorticoids, a dopaminergic mechanism is actively involved in the maintenance of these hemodynamic changes.

Renal response to a protein meal in children with single kidneys.

The renal response of healthy adults to an oral protein load results in a significant increase of renal plasma flow (RPF) and glomerular filtration rate (GFR) 100 to 150 min after the meal. The renal response to protein loading of single kidney adults is unclear and it has not been evaluated yet in children. Therefore, we studied 8 children 10.2 +/- 1.1 years old, 6.7 +/- 1.41 years after nephrectomy (SK) and 4 healthy children (C). RPF was estimated by para-amino-hippurate clearance (Cpah) and GFR by inulin clearance (Cin) before and after an oral protein load of 1.5 g protein/kg body wt and expressed in ml/min/1.73 m2 BSA. Mean baseline Cin were similar in SK and in C (90 +/- 8 vs 103 +/- 12) while baseline Cpah was lower in SK (339 +/- 19 vs 481 +/- 36, p less than 0.005). After the meal GFR and RPF increased significantly in C (155 +/- 18 and 783 +/- 68, p less than 0.005 and p less than 0.05 vs baseline values, respectively) whereas no significant GFR and RPF changes were seen in SK (81 +/- 9 and 350 +/- 42, respectively). However, the 3 SK children with lower protein intake showed a mild vasodilating response. We conclude that in single kidney children hyperfiltration occurs at baseline conditions and the renal response to acute protein loading is partially or completely blunted, being modulated by protein intake.

[Eclampsia induced by skin allografts in spontaneously hypertensive rats]. / Eclampsia inducida por aloinjertos de piel en ratas espontáneamente hipertensas.

In order to develop an experimental model for eclampsia, 22 female inbred Spontaneously Hypertensive Rats (SHR) were grafted with skin from Holtzman males. The implantation of four sequential grafts took place at an interval of ten days. Each SHR was mated with its corresponding skin donor ten days after the last graft. Five non grafted SHR mated with Holtzman males were used as controls. In most of the experimental rats that became pregnant we found changes which consisted in: low number of offspring, stillborn fetuses, abortions and growth delay. Renal function was evaluated before and during pregnancy showing a physiological increase in glomerular filtration of 7.5% (basal = 0.93 +/- 0.12 ml/min, peak = 1.00 +/- 0.12 ml/min) as compared with an increase of 166% (basal = 0.68 +/- 0.22 ml/min, peak = 1.85 +/- 0.33 ml/min) in the control group. Renal histology showed lesions corresponding to disseminated intravascular coagulation. These results indicate that the association of skin grafts and hypertension in these rats affects the normal development of pregnancy and suggest that immunological factors could be involved in experimental eclampsia.

Features of recovery from acute renal failure post-septic abortion and long-term prognosis.

Ten patients with acute renal failure post-septic abortion were studied. Two groups of patients are described in terms of duration of oliguria, number of dialysis per patient and maximal concentration of BUN during the acute episode of tubular necrosis. Despite different oliguric periods, when the patients reached 500 ml of urine volume in 24 hours, the recovery of diuresis was similar in both groups as well as the decrease of BUN concentration at the end of the hemodialysis period. Functional studies were carried out, up to an average of 10.5 years after the acute episode. Mean values for inulin and para-aminohippurate clearances were 107 +/- 11.53 and 534.6 +/- 62.9 ml/min./1.73 m2 in nonoliguric patients or those with a short period of oliguria. These values are not significantly different from the mean values of Wesson for normal women. On the other hand, reductions in both clearances were present in most patients who had a long period of oliguria (GFR: 84.9 +/- 4.2 and RPF: 418.1 +/- 33.1). These results demonstrate that the duration of oliguria at the time acute renal failure occurred is the most important factor influencing the rate and extent of long-term recovery of renal function.

Chronic indomethacin administration and its relation with the renal kallikrein kinin system during rat pregnancy.

The main purpose of the present study was to elucidate the potential role of vasodilator prostaglandins and the kallikrein kinin system in renal hemodynamic changes observed during rat gestation. Nineteen pregnant rats, un-treated and treated with Indomethacin (3 mg/kg body/wt) for 4 days during peak glomerular hyperfiltration, were studied before and during pregnancy. Twenty-two non-pregnant rats were also included as controls. Daily urinary volume, electrolytes and kallikrein excretion and creatinine clearance were measured along the experiment. Baseline creatinine clearance increased by 43% at the beginning of the third week of pregnancy to decline thereafter. Urinary kallikrein rose earlier, at the second week of pregnancy, and decreased near term while at the same time sodium excretion dropped by 30%. Indomethacin treatment prevented both the maximum increment in glomerular filtration rate occurring in normal pregnancy between days 14 to 18 and the physiological near term decline in kallikrein excretion. Furthermore, it induced an increase in sodium excretion in late pregnancy. These results suggest that vasodilator prostaglandins and the kallikrein kinin system may well participate in gestational hyperfiltration and sodium homeostasis of pregnant rats.

Cellular adaptation of the rat medullary thick ascending limb to chronic renal failure.

Chronic renal failure (CRF) is accompanied by adaptive changes in renal and extrarrenal epithelial ionic transport. Fluid reabsorption in the thick ascending limb of Henle is increased and the capacity to lower the urine osmolality in water diuresis is preserved. To study the cellular mechanism of this adaptation, we measured intracellular cAMP in microdissected medullary thick ascending limb (mTAL) segments in rats with CRF. mTAL exhibited in CRF nephrons an increase of basal cAMP from 6.0 +/- 1.5 in controls to 47.0 +/- 10.3 fmol. mm-1 tubule in CRF (P < 0.05). Maximally stimulated cAMP levels (10(-3) M IBMX plus 10(-5) M Forskolin) were different from basal levels in controls (6.0 +/- 1.5 vs 63.1 +/- 18.8, P < 0.05) but not from basal levels in CRF (47.0 +/- 10.3 vs 63.0 +/- 16.0, P = N.S.). Preincubation with the adenylate cyclase inhibitor 2'5'-dideoxyadenosine (DDA) 10(-4) M produced no changes in cAMP in controls (93.7 +/- 10.3% of DDA untreated samples) whereas it decreased to 76.2 +/- 8.8% (24% inhibition) in CRF (P < 0.05). No differences between controls and CRF groups were found in basal and stimulated cAMP in red blood cells and distal colon. The data would suggest that the cAMP pathway is an intracellular signal for mTAL adaptation in epithelial transport and that the adenylate-cyclase system is specifically activated in CRF.

Protein restriction and progression of chronic renal failure.

The effect of protein restriction upon the rate of renal functional decline was studied in 7 patients with moderate chronic renal failure (CRF). The rate of progression of CRF was evaluated by the reciprocal of plasma creatinine concentration (1/Cr) in time method, every 1-3 months, during 12 months while on ad-libitum diet and 23-40 months thereafter while on protein restriction. While on ad-libitum diet, 4/7 patients showed a progressive disease and the other 3 showed a relatively stable evolution. Six months after protein restriction, patients with a previous progressive disease showed an amelioration in the decline in renal function, and those with stable CRF showed a worsening of the disease in two cases and an improvement in the other one. During the first six months on low protein diet, a transitory increase in plasma creatinine concentration was observed, being maximum at 2.7 months. Plasma urea concentration fell, after protein restriction, to values close to that predicted at the time of the prescription of the diet. Mean systolic and diastolic arterial blood pressure remained stable throughout the study and it was not necessary to change the pharmacological treatment. Our data show that protein restriction decreases the rate of progression of CRF in patients with previous progressive disease. This benefit may result from the suppression of compensatory hyperfiltration induced by low protein diet, as suggested by the increase in plasma creatinine concentration.

[Autosomal dominant polycystic kidney disease: detection of a new mutation in the PKD1 gene]. / Poliquistosis renal autosómica dominante. Detección de una nueva mutación en el gen PKD1.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by genetic heterogeneity. Up to three loci are involved in this disease, PKD1 on chromosome 16p13.3, PKD2 on 4q21, and a third locus of unknown location. Since the identification of the PKD1 gene, the interest was centered in the characterization of the mutations responsible for the disease. Most mutations found were diverse and situated throughout the gene with no phenotypic correlation. Here we describe a new mutation in exon 44 from PKD1 gene in a family previously characterized as PKD1 by linkage analysis. The mutation is a single base substitution from a C to a T at position 12220 originating a stop codon at the mutation site. This would lead to premature termination and the formation of a truncated protein lacking part of the carboxi-terminus.

Depressed eruption dental rate in rats with hemodynamically-mediated acute renal failure.

The effects of acute renal failure on the impeded (IER) and unimpeded (UER) eruption dental rate and attrition rate (AR) were investigated. Adult female Wistar rats were injected with 125 mg/kg b.w of human methemoglobin (M-Hb) in order to induce a first episode of hemodynamically-mediated acute renal failure (H-ARF). Ten days after the injection of M-Hb, other groups of rats received another equal dose of the drug in order to induce a second episode of H-ARF. A group of six animals was pair-fed daily and individually with rats of M-Hb groups. Evaluation of renal function, histopathology studies, IER, UER, food intake (FI), AR and body weight gains was performed at different times after the first and second injections, of M-Hb. Treatment induced transient increases in plasma urea concentration and urine volume, and significant depression in urine osmolality, body weight gains, IER, UER and AR. In every case, the maximal effect of the first injection of M-Hb on the individual parameters was always greater than that of the second injection. Histologic sections showed interstitial cellular infiltration, desquamation of the proximal tubular epithelium and collapse or dilation of the tubular lumen. The functional values of kidney, histologic findings, IER, UER and AR of the pair-fed rats were not significantly different from control values. The results of the present study indicate that dental eruption rate (IER and UER) is relatively low in uremic rats with kidney tubule lesions and that both parameters are related.

Low sodium intake induces an increase in renal monoamine oxidase activity in the rat. Involvement of an angiotensin II dependent mechanism.

AIMS: The interplay between natriuretic dopamine and antinatriuretic angiotensin II represents an important mechanism for the regulation of renal sodium and water excretion. Monoamine oxidase is the main metabolizing pathway for dopamine in the renal cortex. In this study, we have analysed the effect of low sodium feeding and AT1 receptor blockade on renal dopamine metabolism by monoamine oxidase. METHODS: Four groups of rats were studied: 1, normal salt diet (NS); 2, low salt diet (LS); 3, NS receiving Losartan (Los, specific AT1 receptor antagonist, 20 mg kg(-1) bwt day(-1), NS + Los); 4, LS receiving Los (LS + Los). RESULTS: Urinary dopamine excretion was lower in LS than in NS rats (543 +/- 32 vs. 680 +/- 34 ng day(-1) 100 g(-1) bwt, P < 0.05). When treated with Los, DOPAC excretion and urinary DOPAC/dopamine ratio fell significantly in the LS + Los group as compared with the LS group (1199 +/- 328 vs. 3081 +/- 681 ng day(-1) 100 g(-1) bwt and 1.90 +/- 0.5 vs. 5.7 +/- 1.2, respectively, both P < 0.02). Losartan increased hydroelectrolyte excretion in the LS group. No changes were found in the NS + Los group. Aromatic L-amino acid decarboxylase activity in cortex was similar in NS and LS rats. Instead, monoamine oxidase activity was higher in cortical homogenates from LS rats (in nmol mg tissue(-1) h(-1): NS 7.66 +/- 0.52; LS 9.82 +/- 0.59, P < 0.05) and this difference was abolished in LS + Los rats (7.34 +/- 0.49 nmol mg tissue(-1) h(-1), P < 0.01, vs. LS). CONCLUSIONS: We have concluded that low levels of dopamine in the urine of LS rats are because of an increase in the activity of renal monoamine oxidase and that angiotensin II mediates this increase through stimulation of AT1 receptors.

Focal glomerulosclerosis in children: an Argentinian experience.

Twenty-six children presenting with idiopathic nephrotic syndrome and a histological diagnosis of focal glomerulosclerosis were studied retrospectively to evaluate their response to treatment, outcome and clinicopathological correlations. Twenty-two patients (84.6%) were steroid resistant; of these, 8 of the 19 with focal segmental glomerulosclerosis and 2 of the 3 with focal global glomerulosclerosis responded to cyclophosphamide (CY) within 16 weeks of starting therapy. Seven patients relapsed after a CY-induced remission, but 5 of them became steroid responsive. After an average follow-up of 83 months, 17 patients are in remission with normal renal function, 3 patients have persistent nephrotic range proteinuria and 6 patients are in chronic renal failure. Persistence of proteinuria, a high percentage of segmentally sclerotic glomeruli and diffuse mesangial proliferation were indicators of poor prognosis. We believe longer courses of CY therapy than those traditionally utilized are responsible for the relatively good results in our patients.

Renal functional reserve in children with a previous episode of haemolytic-uraemic syndrome.

Renal function [creatinine clearance (CCr)] and renal functional reserve (RFR) was measured in 16 children who had had haemolytic-uraemic syndrome (HUS) an average of 6.6 +/- 0.72 years previously. All patients had normal plasma creatinine and blood pressure and only 3 had proteinuria, which was mild in every instance. Patients were studied whilst ingesting three diets which provided an average of 1.5, 2.1 and 3.1 g protein/kg body weight per day, respectively. Diets were administered over three consecutive periods of 7 days each and CCr was measured on the 7th day of each diet. Values tended to correlate with protein intake. They were in the normal range when patients were taking 1.5 and 2.1 g protein diets and increased markedly in 13 of the 16 patients (P less than 0.001) when they ingested the high-protein diet (3.1 g). The effect on glomerular filtration rate (GFR)--measured by CCr and inulin clearance (Cin)--of an acute oral protein load was studied in 12 of the HUS patients and four control subjects. In the control periods, prior to the protein load, values for CCr were similar in the HUS and control subjects (104.0 +/- 11.0 vs 121.6 +/- 10.1 ml/min per 1.73 m2, NS). However Cin values were significantly reduced in HUS patients (59.5 +/- 9.2 vs 102.7 +/- 12.4 ml/min per 1.73 m2, (P less than 0.025). The CCr/Cin ratio in the patients averaged 2.10 compared with 1.13 in controls. Acute protein loading was accompanied by an increase in Cin in all controls but in only 8 of the 12 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in glomerular filtration rate and renal plasma flow in cirrhotic rats during converting enzyme inhibition.

During the development of cirrhosis ascites-edema, peripheral vasodilatation, hypotension and an increase of the plasma concentration of several neurohormones are frequently observed. Such complex changes in the hormonal profile hinders the assessment of the relative role of each in the pathophysiology of this disease. The purpose of this work was to evaluate in a rat model of experimental cirrhosis (phenobarbital/CCl4) the role of the renin-angiotensin system in the pre-ascitic stage of the disease using the converting enzyme inhibitor captopril. Cirrhotic rats showed diminished renal and hepatic perfusion. Compared to normal rats, glomerular filtration rate in cirrhotic rats was reduced from 0.75 +/- 0.11 to 0.42 +/- 0.06 mL/min/100 g BW, and renal plasma flow was reduced from 2.37 +/- 0.28 to 1.58 +/- 0.16 mL/min/100 g BW; the indocyanine green slope changed from -0.095 +/- 0.028 to -0.057 +/- 0.01; the plasma sodium concentration fell from 144 +/- 1.5 to 131 +/- 5.40 mEq/L (all < .05). The mean arterial pressure was not reduced in the cirrhotic rats. There was no ascites. Both the acute (25 mg i.v.) and chronic (25 mg i.p. daily plus 25 mg/L in drinking water) administration of captopril to cirrhotic rats induced an increase in glomerular filtration rate and renal plasma flow along with a steeper slope in indocyanine green decay (p < .05 for all three parameters) when compared to non-treated cirrhotic animals. No changes were observed in controls. In the balance studies, an increase in urinary volume along with a decrease in urinary osmolality was recorded in cirrhotic rats on chronic captopril treatment. In conclusion, our results show an activation of the renin-angiotensin system in these rats, as disclosed by the inhibition of the converting enzyme, as well as a possible interaction with ADH.

Portal pressure, renal function and hormonal profile after acute and chronic captopril treatment in cirrhosis.

The acute effects of captopril in cirrhosis are well known but there are few descriptions of the pattern of response to chronic administration of captopril in this disease. Nine nonuraemic cirrhotic patients with ascites and portal hypertension were studied after 1 week on fixed sodium and water intake (balance diet) and following acute and chronic treatment with captopril (three doses of 25 mg every 30 min and 75 mg.day-1 for three weeks, respectively). Whilst on the balance diet, 7/9 patients were unable to excrete the amount of sodium ingested. After the acute administration of captopril, a significant reduction was seen in arterial blood pressure (86.9 vs 77 mm Hg), with no change in the intra-hepatic pressures (free suprahepatic pressure, FSHP: 15.0 vs 12.1 mm Hg and wedged suprahepatic pressure, WSHP: 22.9 vs 20.7 mm Hg). After chronic captopril treatment, a drop was observed in portal pressure (FSHP: 9.4 mm Hg and WSHP 18.8 mm Hg, NS) and the arterial pressure returned to its basal level. The plasma aldosterone concentration decreased, whilst noradrenaline and dopamine increased significantly, the latter more than the former, leading to a reduction in the noradrenaline/dopamine ratio (14.5 vs 5.0). Seven out of nine patients showed enhanced natriuresis and the remaining two, who previously had had a positive sodium balance failed to do so. These haemodynamic, hormonal and renal changes were interpreted as evidence of blockade of angiotensin II generation by captopril, and also as a homoeostatic response by the sympathetic nervous system.